Clinical Outlook

T cell-based immunotherapies have revolutionized cancer treatment, and strategies to redirect T cells to recognize cancer cells are being investigated both preclinically and clinically. Bispecific T cell-engagers are antibodies that simultaneously bind to an antigen on tumor cells and a surface molecule on T cells. They have shown impressive activity in B cell malignancies and are being explored in many other cancer entities.

Antibody–drug conjugates (ADCs) were first developed in the 1980s, and since then, technical advances have allowed their approval by the US Food and Drug Administration and their use in the treatment of various cancers. In 2022, several new ADCs were developed and tested in clinical trials, with promising results.

Tumors with DNA mismatch repair or proofreading deficiencies, either at the germinal or somatic level, usually present with high tumor mutational burden and often show striking responses to checkpoint blockade immunotherapy. Ongoing translational and clinical investigations of those tumor subsets provide avenues for further improvement in patient outcomes.

Malignant pleural mesothelioma is a challenging disease with few approved treatments. Rapidly expanding insights into the pathogenesis of this cancer and clinical trials are now suggesting a variety of targeted and immune-oncology agents with the potential to address unmet clinical needs.

The rapid progression of KRAS(G12C) inhibitors from preclinical characterization to the clinic has radically changed the perception of the KRAS oncogene as an undruggable target. Here we discuss ongoing and future possibilities for developing therapies using these inhibitors in clinical settings.

Combination of approved immune checkpoint inhibitors has shown remarkable efficacy in the treatment of melanoma, but at the cost of high toxicity. After years of intensive research, inhibitors of the immune checkpoint molecule LAG-3 are now demonstrating promising results and favorable toxicity profiles in clinical trials in combination with inhibition of the checkpoint molecule PD-1.

The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drugs. However, immunotherapy combinations have shown promising activity, targeted chemotherapy options via antibody–drug conjugates are in the clinic, and molecular means of identifying targetable subsets are on the horizon. This Clinical Outlook discusses current and future possibilities for treating triple-negative breast cancer.

Inhibition of the anti-apoptotic protein BCL-2 has emerged as a highly effective treatment for acute myeloid leukemia; approved lower-intensity venetoclax combination therapies are now being rapidly incorporated into an improved standard of care for this cancer. Here we recount an abbreviated history of venetoclax for acute myeloid leukemia, focusing on a selection of key studies along the path from development into the clinic.

Recent preclinical and clinical research has led to exciting advances related to high-grade serous ovarian cancer, from examining its cellular origins to gaining insight into DNA-damage-repair mechanisms that may be leveraged for therapies. Furthermore, studies have demonstrated clinical benefit for inhibition of the polymerase PARP and modulation of the cell cycle, and have identified molecular features related to therapeutic response.